EP4286368A1 - Method for the preparation of 4-formyl-3-methoxybenzonitrile - Google Patents

Abstract

The present invention relates to a process for producing 4-formyl-3-methoxybenzonitrile of the formula (I). Another aspect of the invention is the use of the process according to the invention for producing 4-formyl-3-methoxybenzonitrile of formula (I) for producing finerenone of formula (II). Another aspect of the invention is a process for producing Finernone (II) using the process for producing 4-formyl-3-methoxybenzonitrile of formula (I). Another aspect of the invention is the use of 4-methyl-3-methoxybenzonitrile of formula (III) or 3-methoxy-4-(dibromomethyl)benzonitrile (IV) to produce 4-formyl-3-methoxybenzonitrile of formula (I) . Another aspect of the invention is the use of 4-methyl-3-methoxybenzonitrile of formula (III) or 3-methoxy-4-(dibromomethyl)benzonitrile (IV) for the production of finerenone of formula (II).

Description

4-Formyl-3-methoxybenzonitril (I) ist ein zentraler Baustein bei der Herstellung von Finerenone, (4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carbox-amid, der Formel (II)

The present invention relates to a process for producing 4-formyl-3-methoxybenzonitrile of the formula (I)

4-Formyl-3-methoxybenzonitrile (I) is a central building block in the production of finerenone, (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4- dihydro-1,6-naphthyridine-3-carboxamide, of formula (II)

The compound of formula (II) acts as a non-steroidal antagonist of the mineralocorticoid receptor and is used for the prophylaxis and/or treatment of cardiovascular and renal diseases. The CAS number of Finerenone is CAS 1050477-31-0 . The compound of formula (I) and its production process are, for example, in WO 2008/104306 A1 , ChemMedChem 2012, 7, 1385 and EP 3174875 B1 described. The aldehyde according to the formula (I) is known from the literature, for example in EP 3174875 B1 . In the EP 3174875 B1 The preparation of the compound of formula (I) is described as follows:

In the EP 3174875 B1 the first stage takes place from the compound of formula (1) to the compound of Formula (2) in dimethyl sulfate. The nitrile group is introduced into the compound according to formula (I) in the second stage using palladium catalysis/potassium hexacyanoferrate. The procedure has various disadvantages: Dimethyl sulfate is classified as highly toxic and carcinogenic. The use of the highly toxic and carcinogenic dimethyl sulfate makes upscaling this level on a large scale difficult. Numerous safety measures must be adhered to to ensure safe handling. The starting material bromosalicylic acid of formula (1) is also expensive. Furthermore, the waste to be disposed of must be processed separately to ensure that the dimethyl sulfate is completely destroyed, which leads to increased costs overall.

Further syntheses for the compound of formula (I) are, for example, in WO2007140894 A1 , WO2001000587 A1 , WO2006060461 A1 , US20130072468 A1 , and in Banerjee, Abhisek; et al. Bioorganic & Medicinal Chemistry Letters (2012), 22(9), 3223-3228 described. All of the processes described in these literature references are not suitable for industrial upscaling because, on the one hand, the reagents used contain a potential hazard and/or the resulting waste (e.g. manganese dioxide) is difficult to dispose of.

The production of aldehyde (I), for example, is in Patrick et al, Journal of Medicinal. Chemistry 2007, 50, 2468-2485 , EP1719767 A1 and CN102020587 A described:

In EP'767, starting from 4-cyano-2-methoxytoluene of the formula (III) [compound 64 in EP'767], 3-methoxy-4-(dibromomethyl)benzonitrile is produced with N-bromosuccinimide (NBS) in carbon tetrachloride ( _CCl4 ). of formula (IV) [compound 65 in EP'767], which is converted in ethanol with 2.46 equivalents of silver nitrate to give the aldehyde of formula (I) [compound 44f in EP'767]. In addition, the intermediate dibromide of the formula (IV) (3-methoxy-4-(dibromomethyl)benzonitrile) is purified using an expensive chromatography stage. These syntheses described in the literature and the process described in the research synthesis are not suitable for upscaling to the multi-ton scale. This is particularly true when taking into account the function of silver as an HBr scavenger: the saponification of benzylic dibromides under anhydrous conditions is known per se (DMSO 100°C: Li, Wei; et al Tetrahedron Letters (2004), 45(5), 1071-1074 ). Implementations among the in Li et al. (2004). Conditions , leads to many side reactions due to decomposition, which lead to heavily contaminated products (compare also: DMF: 120°C: Wang, Yongfei; et al Synthesis (2011), (2), 287-291 ). Under anhydrous conditions one observes the cleavage of the methyl ether and also the addition of HBr to the nitrile group, as well as nuclear bromination by-products.

In CN102020587 A The hydrolysis is carried out with dimethyl sulfoxide (as a solvent), which is very difficult to separate from the resulting reaction mixture. There is also a strong odor caused by the formation of dimethyl sulfide, which requires special precautions such as oxidation scrubbers. The aldehyde of formula (I), which is obtained by extraction from ethyl acetate, is simply evaporated to dryness. A crystallization and isolation process is not disclosed anywhere.

The quality of the products resulting from the syntheses discussed above is not sufficient for use in the pharmaceutical industry. Since the aldehyde of the formula (I) is a so-called "regulatory starting material", special requirements must be placed on the purity (> 99%) of this substance. This means that, in addition to the actual synthesis, there is also a downstream crystallization process that ensures high purity and reproducibility. Since all of these requirements are not described in the prior art, there was a great need for a new, more efficient and economically more favorable synthesis that delivers the aldehyde of formula (I) in very high purity for use in a synthesis suitable for the pharmaceutical industry.

A new process has succeeded in meeting the requirements of a scalable process in terms of environmental compatibility of the materials and cost efficiency. The new process can basically be described as follows:

umfassend die Schritte

• Schritt 1) Umsetzen von 4-Methyl-3-Methoxybenzonitril der Formel (III)
  
  mit einem Bromierungsreagenz, wobei 3-Methoxy-4-(dibromomethyl)benzonitril der Formel (IV)
  
  erhalten wird,
• Schritt 2) Hydrolyse von 3-Methoxy-4-(dibromomethylbenzonitril) der Formel (IV)
  
  zu der Verbindung der Formel (I)
  

The invention relates to a process for producing 4-formyl-3-methoxybenzonitrile of the formula (I),

comprehensive the steps

• Step 1) Reacting 4-methyl-3-methoxybenzonitrile of the formula (III)
  
  with a bromination reagent, where 3-methoxy-4-(dibromomethyl)benzonitrile of the formula (IV)
  
  is received,
• Step 2) Hydrolysis of 3-methoxy-4-(dibromomethylbenzonitrile) of formula (IV)
  
  to the compound of formula (I)
  

The terms “4-formyl-3-methoxybenzonitrile” and “compound according to formula (I)” are synonyms. The terms "finerenone", compound of formula (II) and (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine -3-carbox-amide are synonyms. The terms “4-methyl-3-methoxybenzonitrile” and “compound according to formula (III)” are synonyms. The terms “3-methoxy-4-(dibromomethyl)benzonitrile” and “compound according to formula (IV)” are synonyms.

The process according to the invention also has the great advantage that the dibromide of the formula (IV) does not have to be isolated but can be used directly in the subsequent step. Experts also call this direct use without further insulation “telescopic”. This means that the dibromide (II) can be telescoped directly into the following step. For example, this not only saves additional steps and material, but also the use of complex and cost-intensive insulation equipment. The addition of water during the hydrolysis of the dibromide of formula (IV) leads to very pure product of formula (I). Furthermore, there are hardly any by-products or they are only present in very small quantities. The process according to the invention delivers the aldehyde of the formula (I) in very high chemical purity (>99%). This allows this starting material to be used for the synthesis of a drug. In one embodiment, the compound of formula (I) is used for the preparation of the compound of formula (II).

mit einem Bromierungsreagenz umgesetzt, wobei 3-Methoxy-4-(dibromomethylbenzonitril) der Formel (IV)

erhalten wird.In step 1) of the process according to the invention, 4-methyl-3-methoxy-benzonitrile of the formula (III)

reacted with a bromination reagent, whereby 3-methoxy-4-(dibromomethylbenzonitrile) of the formula (IV)

is received.

3-Methoxy-4-methylbenzonitrile of formula (III) is commercially available. The CAS number is CAS 3556-60-3 . The production of the compound of formula (III) is known from the literature (see for example WO2007139992 A2 , Example 1).

It is also possible to use other bromination reagents available on the market in step 1). In principle, bromine-containing amides, bromine-containing imides or mixtures thereof are suitable, in which the bromine is located on the nitrogen atom. In one embodiment, the bromination reagent is selected from N-bromosuccinimide, 1,3-dibromo-5,5-hydantoin, bromine, and mixtures thereof. In one embodiment, the bromination reagent is selected from N-bromosuccinimide, 1,3-dibromo-5,5-hydantoin and bromine. In one embodiment, the bromination reagent is 1,3-dibromo-5,5-hydantoin. In one embodiment, 2 to 3 equivalents of N-bromosucciniimide, based on the starting material (III), are used in step 1). In one embodiment, 2.0 -2.5 equivalents of N-bromosucciniimide, based on the starting material (III), are used in step 1). In one embodiment, 2.1-2.2 equivalents of N-bromosucciniimide, based on the starting material (III), are used in step 1). In one embodiment, 1.0 to 1.5 equivalents of 1,3-dibromo-5,5-hydantoin, based on the starting material (III), are used in step 1). In one embodiment, 1.1 to 1.3 equivalents of 1,3-dibromo-5,5-hydantoin, based on the starting material (III), are used in step 1). In one embodiment, 1.1 to 1.2 equivalents of 1,3-dibromo-5,5-hydantoin, based on the starting material (III), are used in step 1). In one embodiment of step 1), bromine (Br ₂ ) is used as the bromination reagent. In one embodiment of step 1), bromine is used as the bromination reagent in an amount of 1 to 3 equivalents, based on the starting material (III). In one embodiment of step 1), bromine is used as the bromination reagent in an amount of 2.0 to 2.4 equivalents, based on the starting material (III). In one embodiment of step 1), bromine is used as a bromination reagent and irradiated. In one embodiment of step 1), bromine is used as a bromination reagent and irradiated with a diving lamp. When using the diving lamp, the radical start occurs through the light.

In one embodiment, a solvent is used in step 1). The term “solvent” also includes solvent mixtures. In one embodiment, the solvent in step 1) is a chlorinated solvent. In one embodiment, the solvent in step 1) is selected from Chloroform, chlorobenzene, dichlorobenzene and mixtures thereof. In one embodiment, the solvent in step 1) is selected from chlorobenzene, chloroform and mixtures thereof.

In one embodiment, the bromination in step 1) is carried out at temperatures of 50 to 120 ° C. In one embodiment, the bromination in step 1) is carried out at temperatures of 80 to 100 ° C. In one embodiment, the bromination in step 1) is carried out at temperatures of 85 to 95 ° C.

In one embodiment of step 1), a 5 to 15-fold amount of the solvent is used, the amount of solvent being the volume in milliliters (mL), based on 1 gram (g) of starting material used. For example, when using 5 times the amount of solvent, 5 mL of the solvent is used for 1 g of the compound according to formula (III). In one embodiment of step 1), an 8-10 times the amount of solvent is used, the amount of solvent being the volume in mL, based on 1 g of starting material used.

In one embodiment of step 1), a radical starter will be used. Radical starters are well known in the literature. They can be used to start the reaction in a controlled manner. In one embodiment, the radical initiator is selected from dibenzoyl peroxide and azobisisobutyronitrile. In one embodiment of step 1), the radical initiator is dibenzoyl peroxide. In one embodiment of step 1), the radical initiator is azobisisobutyronitrile. It is also possible to use other radiac starters available on the market. Reactive peroxides, reactive azo compounds or light can be used.

In one embodiment of step 1), the radical initiator is used in a catalytic amount. In one embodiment of step 1), the radical initiator is used in an amount of 0.03 to 0.15 equivalents, based on the starting material (III). In one embodiment of step 1), the radical initiator is used in an amount of 0.05 to 0.1 equivalents, based on the starting material (III). In one embodiment of step 1), the radical initiator is used in an amount of 0.05 equivalents, based on the starting material (III). In addition to the radical initiator, a small amount of elemental bromine can be added. In one embodiment of step 1), elemental bromine is additionally used in an amount of 0.01 equivalent, based on the starting material (III).

In one embodiment of step 1), the reaction time is 3 to 8 hours. In one embodiment of step 1), the reaction time is 4 to 5 hours.

To work up the reaction mixture or the product from step 1), it can be washed with water and/or a sodium sulfite or sodium hydrogen sulfite or sodium thiosulfate solution, the precipitated solids are filtered off and the solvent is distilled off to the stirrability limit become.

zu der Verbindung der Formel (I)

hydrolysiert.In step 2) of the process according to the invention, 3-methoxy-4-(dibromomethylbenzonitrile) of the formula (IV)

to the compound of formula (I)

hydrolyzed.

Hydrolysis has great advantages over the processes described in the prior art, such as (AgNO3: J. Med. Chem. 2007, 50, 2468-2485 , EP1719767 A1 ).

In one embodiment, the product obtained in step 1), which comprises the compound of formula (IV), is used directly in the next step 2). In one embodiment, the compound of formula (IV) is isolated from the product obtained in step 1). The isolation can be carried out, for example, by crystallization. The isolated compound of formula (IV) can then be hydrolyzed in step 2) to the compound of formula (I). In one embodiment of step 2), the hydrolysis is an aqueous hydrolysis.

In one embodiment of step 2), the hydrolysis of the dibromide of formula (IV) is carried out in a solvent. The term “solvent” also includes solvent mixtures. In one embodiment of step 2), solvent is selected from water, dimethylformamide, dimethylacetamide, N-methylpyrolidone (NMP), tetramethylurea, chlorobenzene, dichlorobenzene and mixtures thereof. In one embodiment of step 2), solvent is selected from water, chlorobenzene, chloroform, dimethylformamide and mixtures thereof. In one embodiment of step 2), solvent is selected from chlorobenzene, chloroform, dimethylformamide and mixtures thereof.

In one embodiment of step 2), the solvent is a solvent mixture comprising water and a solvent. In one embodiment of step 2), the solvent is a solvent mixture comprising water and a solvent selected from dimethylacetamide, N-methylpyrolidone (NMP), tetramethylurea, chlorobenzene, dichlorobenzene and mixtures thereof. In one embodiment of step 2), the solvent is a solvent mixture comprising water and a solvent selected from chlorobenzene, chloroform, dimethylformamide and mixtures thereof. In one embodiment of step 2), the solvent is a solvent mixture consisting of water and a solvent. In one embodiment of step 2), the solvent is a solvent mixture consisting of water and a solvent selected from dimethylacetamide, N-methylpyrolidone (NMP), tetramethylurea, chlorobenzene, dichlorobenzene and mixtures thereof. In one embodiment of step 2), the solvent is a solvent mixture consisting of water and a solvent selected from chlorobenzene, chloroform, dimethylformamide and mixtures thereof. In one embodiment of step 2), the solvent is a solvent mixture consisting of water and a solvent, the volume ratio of water to solvent being selected from 1:3, 1:2 and 1:1. In one embodiment of step 2), the solvent is a solvent mixture consisting of dimethylformamide and water. In one embodiment of step 2), the solvent is a solvent mixture consisting of dimethylformamide and water, the volume ratio of dimethylformamide to water being 1 to 1.5:1. In one embodiment of step 2), the solvent is a solvent mixture consisting of chlorobenzene and water. In one embodiment of step 2), the solvent is a solvent mixture consisting of chlorobenzene and water, the volume ratio of chlorobenzene to water being 1.5:1. In one embodiment of step 2), the solvent is a solvent mixture consisting of chloroform and water. In one embodiment of step 2), the solvent is a solvent mixture consisting of chloroform and water. In one embodiment of step 2), the solvent is a solvent mixture consisting of chloroform and water, the volume ratio of chlorobenzene to water being 1.5:1.

Step 2) can take place in a homogeneous phase or two-phase implementation. In a two-phase reaction, stirring can be carried out intensively so that thorough mixing can occur. To carry out step 2) in practice, an excess of the solvent can, if necessary, be added first and distilled off to the target volume. Water with acidic or basic additives can then be added.

In one embodiment of step 2), an acidic additive is added to the reaction mixture. In one embodiment of step 2), an acidic additive selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid and mixtures thereof is added to the reaction mixture.

In one embodiment of step 2), a basic additive selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, pyridine, triethylamine, ammonia and mixtures thereof is added to the reaction mixture. In one embodiment of step 2), a basic additive selected from sodium hydroxide, sodium carbonate, sodium bicarbonate and mixtures thereof can also be added to the reaction mixture.

In step 2) the solvents or solvent mixtures mentioned under step 1) or step 2) can be used. This also applies the other way around.

In one embodiment of step 2), the hydrolysis takes place at temperatures of 80 to 100 ° C. In one embodiment of step 2), the hydrolysis takes place at temperatures of 85 to 95 ° C. In one embodiment of step 2), the hydrolysis takes place at 90 ° C.

In one embodiment of step 2), the reaction time is 2 to 6 hours. In one embodiment of step 2), the reaction time is 3 to 4 hours. In one embodiment of step 2), the reaction time is 4 hours.

To work up the product obtained in step 2), water and/or an inorganic or organic base can be added, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, pyridine, triethylamine, ammonia. In one embodiment, sodium carbonate and/or sodium bicarbonate is used. If necessary, it can also be washed with sodium sulfite, sodium hydrogen sulfite or sodium thiosulfate solution. You can add the base in dissolved form in water. If necessary, the pH can be adjusted by adding an acid. In one embodiment, the pH is adjusted to 5-8. In one embodiment, the pH is adjusted to 7. In one embodiment, the acid is hydrochloric acid.

After step 2), the connection can be extracted. In one embodiment, the method includes step 1), step 2) and an extraction step. In one embodiment of the extraction step, the compound of formula (I) can be extracted with a water-immiscible solvent. In one embodiment, the solvent is selected from ethyl acetate, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), methyl tert-butyl ether (MTBE), isopropyl acetate, THF, 2-methyl-THF dichloromethane and mixtures thereof. In one embodiment, the solvent is selected from MIBK, ethyl acetate, chlorobenzene and mixtures thereof.

Following step 2), a further purification step can be carried out. This can be done after step 2) or the extraction step. In one embodiment, the purification step is a crystallization step.

In one embodiment, the method includes step 1), step 2), an extraction step and a purification step. In one embodiment, the method includes step 1), step 2) and a purification step. In one embodiment, the method includes step 1), step 2), an extraction step and a crystallization step. In one embodiment, the method includes step 1), step 2) and a crystallization step. In one embodiment of the crystallization step, a solvent selected from ethyl acetate, methyl tert-butyl ether (MTBE), isopropyl acetate, isobutyl methyl ketone (MIBK), hexane, cyclohexane, methylcyclohexane, heptane, acetone, chlorobenzene, toluene, dichloromethane and mixtures thereof is used. In one embodiment of the crystallization step, a solvent selected from ethyl acetate, methyl tert-butyl ether (MTBE), isopropyl acetate, isobutyl methyl ketone (MIBK) and mixtures thereof is used. In the crystallization step, a solvent selected from hexane, cyclohexane, methylcyclohexane, heptane, acetone, ethyl acetate, chlorobenzene, isobutyl methyl ketone (MIBK), methyl tert-butyl ether (MTBE), toluene and mixtures thereof is used. In one embodiment of the crystallization step, a solvent selected from heptane, chlorobenzene, isobutyl methyl ketone (MIBK), ethyl acetate, dichloromethane or mixtures thereof is used. In one embodiment of the crystallization step, crystallization takes place from ethyl acetate. In one embodiment of the crystallization step, one or more of the solvents or solvent mixtures mentioned under step 1) or step 2) will be used.

In one embodiment of the crystallization step, the crystallization is carried out at temperatures of 20 to -5 ° C. In one embodiment of the crystallization step, the crystallization is carried out at temperatures of -10 to -15 ° C.

In one embodiment of the crystallization step, a highly concentrated, supersaturated solution containing the compound according to formula (I) is dissolved in ethyl acetate, methyl tert-butyl ether (MTBE), isopropyl acetate, isobutyl methyl ketone or mixtures thereof at low temperatures of -20 to -5 ° C or -10 to -15 ° C with the aldehyde according to the formula (I). In a variant of this embodiment, ≤0.01 equivalent 1 of the aldehyde according to the formula (I) is seeded. The inoculation results in controlled crystallization during subsequent stirring.

The crystallized aldehyde of the formula (I) can further be isolated. In one embodiment, isolation can be done by filtration. In another embodiment, this can be done using a centrifuge. However, other isolation methods are known from the literature and can be used. The isolated compound according to formula (I) can optionally be washed with a little cold solvent. In one embodiment, these usable solvents are selected from heptane and chlorobenzene, isobutyl methyl ketone (MIBK), ethyl acetate, dichloromethane and mixtures thereof.

In a further step, the compound of formula (I) can be dried after one or more of the aforementioned steps. The drying compound of formula (I) can be carried out at 20 to 55 ° C or 45 to 50°C. In a further embodiment of drying, work is carried out in a vacuum. In one example of this embodiment, nitrogen is used as the carrier gas. A pressure of 20 to 50 mbar can be used.

1. (i) Umsetzung von 4-Formyl-3-Methoxybenzonitril der Formel (I) mit einer Bisulfitverbindung, wobei das Addukt nach Formel (V)
   
   erhalten wird,
2. (ii) basische Spaltung des Addukts nach Formel (V), wobei 4-Formyl-3-Methoxybenzonitril der Formel (I) erhalten wird.

In one embodiment, the process further comprises an intermediate purification step of the compound according to formula (I) after step 2). In one embodiment, the purification step includes the steps

1. (i) Reaction of 4-formyl-3-methoxybenzonitrile of the formula (I) with a bisulfite compound, the adduct according to formula (V)
   
   is received,
2. (ii) basic cleavage of the adduct according to formula (V), giving 4-formyl-3-methoxybenzonitrile of formula (I).

The compound of formula (V) represents a bisulfite adduct. In one embodiment, the bisulfite compound in step (i) is selected from NaHSO ₃ , KHSO ₃ and mixtures thereof. In one embodiment of step (i), the solvents mentioned under step 2) are used. Other mixtures with alcohols are possible. Examples of alcohols are methanol, ethanol, isopropanol and mixtures thereof.

In step (ii), the compound of formula (V) is cleaved back into the aldehyde of formula (I) under basic conditions. Optionally, the compound of formula (V) can first be isolated and then subjected to basic cleavage.

In one embodiment, the method comprises step 1), step 2), an extraction step and a purification step comprising steps (1) and (ii). In one embodiment, the method comprises step 1), step 2) and a purification step comprising steps (1) and (ii). In one embodiment, the method comprises step 1), step 2), an extraction step, a crystallization step and a purification step comprising steps (1) and (ii). In one embodiment, the method comprises step 1), step 2), a crystallization step and a purification step comprising steps (1) and (ii).

For the intermediate purification of the aldehyde according to the formula (I), comprising steps (i) and (ii), a reaction can also be carried out to give a bisulfite adduct (V) with NaHSO ₃ or KHSO ₃ , in each case the adduct according to the formula ( Va) or (Vb) forms:

For example, the use of bisulfites Kissane, Marie G.; et al. Tetrahedron Letters (2013), 54(48), 6587-6591 described. The bisulfite adduct according to formula (V) is prepared in water in combination with the solvent used in step 2). This can also be done in two phases. In some cases the organic solvent is continuously distilled off. The bisulfite adduct according to formula (V) is isolated and then split back into the aldehyde according to formula (I) under basic conditions. Suitable bases for this are sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium phosphate, and the respective potassium analogues. The bases that were already mentioned under step 1) or step 2) can also be used. After cleavage, the aldehyde according to formula (I) is extracted into an organic solvent, preferably ethyl acetate, and then the crystallization process is carried out; this can optionally be redistilled to another solvent. “Redistilling” also means a so-called solvent exchange or so-called “solvent switch”.

wobei das Verfahren die folgenden Schritte 1) und 2) umfasst:A further aspect of the invention is a process for producing finerenone according to formula (II),

wherein the method comprises the following steps 1) and 2):

Step 1) Reacting 4-methyl-3-methoxybenzonitrile of the formula (III)

mit einen Bromierungsreagenz, wobei 3-Methoxy-4-(dibromomethyl)benzonitril der Formel (IV)

erhalten wird,

with a bromination reagent, where 3-methoxy-4-(dibromomethyl)benzonitrile of the formula (IV)

is received,

Step 2) Hydrolysis of 3-methoxy-4-(dibromomethylbenzonitrile) of formula (IV)

zu der Verbindung der Formel (I)

to the compound of formula (I)

Embodiments of step 1) and step 2) have already been described above.

In one embodiment, the process for producing finerenone (II) comprises steps 1), 2) and 3):

Step 3) Reacting the compound according to formula (I)

mit der Verbindung der Formel (VII)

wobei die Verbindungen (VIIIa), (VIIIb)

erhalten werden.

with the compound of formula (VII)

where the compounds (VIIIa), (VIIIb)

be received.

In one embodiment of step 3), a solvent is used. In one embodiment of step 3), a secondary alcohol is used as the solvent. In one embodiment of step 3), a solvent selected from isopropanol, isobutanol, 2-amyl alcohol, cyclohexanol and mixtures thereof is used. In one embodiment of step 3), isopropanol is used as the solvent.

In one embodiment of step 3), the solvent is used in a 3 to 9-fold amount, the amount of solvent being the volume in milliliters (mL), based on 1 gram (g) of starting material (I) used. In one embodiment of step 3), the solvent is used in a 3 to 8-fold amount, the amount of solvent being the volume in milliliters (mL), based on 1 gram (g) of starting material (I) used. In one embodiment of step 3), the solvent is used in a 5 to 7-fold amount, the amount of solvent being the volume in milliliters (mL), based on 1 gram (g) used Starting material (I) is. In one embodiment of step 3), isopropanol is used as the solvent in a 3 to 9-fold amount, the amount of solvent being the volume in milliliters (mL), based on 1 gram (g) of starting material (I) used. In one embodiment of step 3), isopropanol is used as the solvent in a 3 to 8-fold amount, the amount of solvent being the volume in milliliters (mL), based on 1 gram (g) of starting material (I) used.

In one embodiment of step 3), isopropanol is used in a 3 to 8-fold amount and 0.05 to 0.10 equivalents of piperidine, in each case based on the starting material (I). In one embodiment of step 3), isopropanol is used in a 3 to 8-fold amount, 0.05 to 0.10 equivalents of piperidine and 0.05 to 0.10 equivalents of glacial acetic acid, each based on the starting material (I). In one embodiment of step 3), isopropanol is dissolved in a 3 to 8-fold amount, 0.05 to 0.10 equivalents of piperidine and 0.05 to 0.10 equivalents of glacial acetic acid, each based on the starting material (I), at 30 ° C. In one embodiment of step 3), 1 to 2 equivalents of the compound of formula (VII), based on the starting compound (I), are used. In one embodiment of step 3), 1 to 1.5 equivalents of the compound of formula (VII), based on the starting compound (I), are used. In one embodiment of step 3), 1.2 to 1.4 equivalents of the compound of formula (VII), based on the starting compound (I), are used.

In one embodiment, the process for producing finerenone (II) comprises steps 1), 2), 3) and 4)

Step 4) Reacting the compounds of the formulas (VIIIa), (VIIIb)

mit Amino-Methyl-Pyridonder Formel (IX)

wobei die Verbindung der Formel (X)

erhalten wird.

with amino-methyl-pyridone of the formula (IX)

where the compound of formula (X)

is received.

In one embodiment of step 4), 0.2 to 2.2 equivalents of the compound of formula (IX), based on the starting compound (VIIIa, VIIIb), are used. If the term “based on the starting compound (VIIIa, VIIIb)” is mentioned here, then reference is made to the total amount of both compounds (VIIIa) and (VIIIb). In one embodiment of step 4), 0.5 to 1.5 equivalents of the compound of formula (IX), based on the starting compound (VIIIa, VIIIb), are used. In one embodiment of step 4), 0.5 to 1.5 equivalents of the compound of formula (IX), based on the starting compound (VIIIa, VIIIb), are used. In one embodiment of step 4), 0.7 to 1.2 equivalents of the compound of formula (IX), based on the starting compound (VIIIa, VIIIb), are used. In one embodiment of step 4), 0.8 to 1 equivalent of the compound of formula (IX), based on the starting compound (VIIIa, VIIIb), is used.

In one embodiment of step 4), a solvent is used. In one embodiment of step 4), a secondary alcohol is used as the solvent. In one embodiment of step 4), a solvent selected from isopropanol, isobutanol, 2-amyl alcohol, cyclohexanol and mixtures thereof is used. In one embodiment of step 3), isopropanol is used as the solvent.

In one embodiment of step 4), the solvent is used in a 3 to 120-fold amount, the amount of solvent being the volume in milliliters (mL), based on 1 gram (g) of starting material (VIIIa, VIIIb) used. When the term “based on 1 gram (g) of starting material (VIIIa, VIIIb)” is mentioned here, reference is made to the total amount of both compounds (VIIIa) and (VIIIb). For example, when using 3 times the amount of solvent, 3 mL of the solvent is used for 1 g (total weight) of the compounds according to formulas (VIIIa) and (VIIIb). In one embodiment of step 4), the solvent is used in a 5 to 18-fold amount, the amount of solvent being the volume in milliliters (mL), based on 1 gram (g) of starting material (VIIIa, VIIIb) used. In one Embodiment of step 4), the solvent is used in an 8 to 15-fold amount, the amount of solvent being the volume in milliliters (mL), based on 1 gram (g) of starting material (VIIIa, VIIIb) used. In one embodiment of step 4), the solvent is used in an 8.5 to 14-fold amount, the amount of solvent being the volume in milliliters (mL), based on 1 gram (g) of starting material used (VIIIa, VIIIb), is. In one embodiment of step 4), the solvent is used in an 8 to 10-fold amount, the amount of solvent being the volume in milliliters (mL), based on 1 gram (g) of starting material (VIIIa, VIIIb) used. In one embodiment of step 4), isopropanol is used as the solvent in an 8 to 15-fold amount, the amount of solvent being the volume in milliliters (mL), based on 1 gram (g) of starting material used (VIIIa, VIIIb). . In one embodiment of step 4), isopropanol is used as the solvent in an 8.5 to 14-fold amount, the amount of solvent being the volume in milliliters (mL), based on 1 gram (g) of starting material (VIIIa, b) used. , is. In one embodiment of step 4), isopropanol is used as the solvent in a 9 to 10-fold amount, the amount of solvent being the volume in milliliters (mL), based on 1 gram (g) of starting material (VIIIa, VIIIb) used .

In one embodiment of step 4), the step is carried out at a temperature of 70 to 130°C. In one embodiment of step 4), the step is carried out at a temperature of 80 to 120°C. In one embodiment of step 4), the step is carried out at a temperature of 90 to 110°C. In one embodiment of step 4), the step is carried out at a temperature of 95 to 105°C. In one embodiment of step 4), the step is carried out at a temperature of 100°C.

In one embodiment, the process for producing finerenone (II) comprises steps 1), 2), 3), 4) and 5)

Step 5) Reacting the compound of formula (X)

zu der Verbindung der Formel (XI)

to the compound of the formula (XI)

In one embodiment of step 5), the reaction takes place under acid catalysis. In one embodiment of step 5), the reaction takes place with the addition of an acidic catalyst selected from sulfuric acid, orthoesters and mixtures thereof. In one embodiment of step 5), the reaction takes place with the addition of an acidic catalyst selected from sulfuric acid, triethyl orthoacetate and mixtures thereof. In one embodiment of step 5), the reaction takes place with the addition of triethylorthoacetate.

In one embodiment of step 5), 2 to 5 equivalents of the acid catalyst compound, based on the starting compound (X), are used. In one embodiment of step 5), 2 to 4 equivalents of the acid catalyst compound, based on the starting compound (X), are used. In one embodiment of step 5), 2 to 3 equivalents of the acid catalyst compound, based on the starting compound (X), are used. In one embodiment of step 5), 2 to 5 equivalents of triethylorthoacetate, based on the starting compound (X), are used. In one embodiment of step 5), 2 to 4 equivalents of triethylorthoacetate, based on the starting compound (X), are used. In one embodiment of step 5), 2 to 3 equivalents of triethylorthoacetate, based on the starting compound (X), are used.

In one embodiment of step 5), a solvent is used. In one embodiment of step 5), a solvent selected from dimethylacetamide, NMP (N-methyl-2-pyrrolidone), DMF (dimethylformamide) and mixtures thereof is used. In one embodiment of step 5), a solvent selected from dimethylacetamide, NMP (N-methyl-2-pyrrolidone) and mixtures thereof is used. In one embodiment of step 5), dimethylacetamide is used as the solvent. In one embodiment of step 5), NMP (N-methyl-2-pyrrolidone) is used as the solvent.

In one embodiment of step 5), the step is carried out at a temperature of 80 to 120 ° C. In one embodiment of step 5), the step is carried out at a temperature of 100 to 120 °C. In one embodiment of step 5), the step is carried out at a temperature of 90 to 110 ° C. In one embodiment of step 5), the step is at a temperature carried out from 95 to 105 °C. In one embodiment of step 5), the step is carried out at a temperature of 100°C.

In one embodiment of step 5), the reaction time is between 1 and 4 hours. In one embodiment of step 5), the reaction time is between 1 and 3 hours. In one embodiment of step 5), the reaction time is between 1.5 and 2.5 hours. In one embodiment of step 5), the reaction time is 2 hours.

In one embodiment of step 5), 2.5 to 5 equivalents of triethylorthoacetate in dimethylacetamide are used at 100 to 120 ° C for 1.5 to 3 hours. In one embodiment of step 5), 2.5 to 5 equivalents of triethylorthoacetate in NMP (N-methyl-2-pyrrolidone) are used at 100 to 120 ° C for 1.5 to 3 hours.

In one embodiment, the process for producing finerenone (II) comprises steps 1), 2), 3), 4), 5) and 6)

Step 6) Saponification of the compound of formula (XI)

zu der Verbindung der Formel (XII)

to the compound of the formula (XII)

In one embodiment of step 6), a solvent is used. In one embodiment of step 6), a solvent selected from water, tetrahydrofuran (THF), 2-methyl-tetrahydrofuran, dioxane, 1,2-dimethoxyethane and mixtures thereof is used. In one Embodiment of step 6), a solvent selected from water, tetrahydrofuran (THF) and mixtures thereof is used. In one embodiment of step 6), a solvent mixture of water and tetrahydrofuran (THF) is used.

In one embodiment of step 6), the solvent is a solvent mixture comprising water and a solvent, the volume ratio of solvent to water being selected from 0.2 to 3: 1 to 2. In one embodiment of step 6), the solvent is a solvent mixture consisting of water and a solvent, the volume ratio of solvent to water being selected from 0.4 to 1.5: 1.

In one embodiment of step 6), the solvent is a solvent mixture consisting of water and THF, the volume ratio of THF to water being selected from 0.4 to 1.5: 1. In one embodiment of step 6), the solvent is a solvent mixture consisting of water and THF, the volume ratio of THF to water being selected from 0.8 to 1.5: 1. In one embodiment of step 6), the solvent is a solvent mixture consisting of water and THF, the volume ratio of THF to Water is selected from 1:1.

In one embodiment of step 6), the solvent is used in a 6 to 15-fold amount, the amount of solvent being the volume in milliliters (mL), based on 1 gram (g) of starting material (XI) used. In one embodiment of step 6), the solvent is used in a 7 to 10-fold amount, the amount of solvent being the volume in milliliters (mL), based on 1 gram (g) of starting material (XI) used. In one embodiment of step 6), the solvent is used in an 8 to 10-fold amount, the amount of solvent being the volume in milliliters (mL), based on 1 gram (g) of starting material (XI) used. In one embodiment of step 6), the solvent is used in a 7 to 10-fold amount, where the amount of solvent is the volume in milliliters (mL), based on 1 gram (g) of starting material (XI) used, and where the The solvent selected is water, THF and mixtures thereof. In one embodiment of step 6), the solvent is used in an 8 to 10-fold amount, where the amount of solvent is the volume in milliliters (mL), based on 1 gram (g) of starting material (XI) used, and where the The solvent selected is water, THF and mixtures thereof.

In one embodiment of step 6), the step takes place in a THF/water mixture in a ratio of 0.6-2:1 in a 7 to 10-fold amount. In one embodiment of step 6), the step is carried out in a THF/water mixture in a ratio of 0.6-2:1 in a 7 to 10-fold amount with the addition of a base. In one embodiment of step 6), the step takes place in a THF/water mixture in a ratio of 0.6-2:1 in a 7 to 10-fold amount with the addition of sodium hydroxide solution.

In one embodiment, the process for producing finerenone (II) comprises steps 1), 2), 3), 4), 5), 6) and 7)

Step 7) Reacting the compound of formula (XII)

in THF mit Carbodiimidazol und 4-(Dimethylamino)-pyridin

in THF with carbodiimidazole and 4-(dimethylamino)-pyridine

In one embodiment of step 7), a solvent selected from THF, 2-methyl-THF, dioxane, 1,2-dimethoxyethane and mixtures thereof is used. In one embodiment of step 7), THF is used as the solvent. In one embodiment of step 7), 4-(dimethylamino)pyridine is used in catalytic amounts. In one embodiment of step 7), this step takes place in a one-pot reaction.

In one embodiment, the process for producing finerenone (II) comprises steps 1), 2), 3), 4), 5), 6), 7) and 8)

Step 8) Heating the product obtained in step 7).

In one embodiment of step 8), the step is carried out with the addition of hexamethyldisilazane. In one embodiment of step 8), the step is carried out with the addition of 3.0 to 4.5 equivalents of hexamethyldisilazane, based on the starting material (XII). In one embodiment of step 8), the step is carried out with the addition of 3.2 to 4 equivalents of hexamethyldisilazane, based on the starting material (XII). In one embodiment of step 8) heating is carried out for 16 to 24 hours. In one embodiment of step 8), 3.0 to 4.5 equivalents of hexamethyldisilazane, based on the starting material (XII), are heated for 16 to 24 hours. In one embodiment of step 8), the step is heated for 16 to 24 hours with the addition of 3.2 to 4 equivalents of hexamethyldisilazane, based on the starting material (XII).

In one embodiment, the process for producing finerenone (II) comprises steps 1), 2), 3), 4), 5), 6), 7), 8) and 9)

Step 9) Hydrolysis of the product obtained in step 8) to the compound of formula (XIII)

In one embodiment of step 9), a solvent is used. In one embodiment of step 8), the solvent is selected from water, THF, 2-methyl-THF, dioxane, 1,2-dimethoxyethane and mixtures thereof.

In one embodiment of step 9), the solvent is a solvent mixture consisting of water and THF. In one embodiment of step 9), the solvent is a solvent mixture consisting of water and THF, the THF being used in a 3 to 7-fold amount and water in a 0.2 to 1-fold amount, the amount of each Solvent is the volume in milliliters (mL), based on 1 gram (g) of starting material used. In one embodiment of step 9), the solvent is a solvent mixture consisting of water and THF, the THF being used in a 4 to 6-fold amount and water in a 0.2 to 0.8-fold amount, the amount of the respective solvent is the volume in milliliters (mL), based on 1 gram (g) of starting material used. In one embodiment of step 9), the solvent is a solvent mixture consisting of water and THF, the THF being used in a 4.5 to 5.5-fold amount and water in a 0.3 to 0.5-fold amount , where the amount of the respective solvent is the volume in milliliters (mL), based on 1 gram (g) of starting material used.

• die Schritte 1), 2), und
• einen oder mehrere der Schritte ausgewählt aus Schritt 3), Schritt 4), Schritt 5), Schritt 6), Schritt 7), Schritt 8) und Schritt 9).

In one embodiment, the process for producing finerenone (II) comprises

• steps 1), 2), and
• one or more of the steps selected from step 3), step 4), step 5), step 6), step 7), step 8) and step 9).

In one embodiment, the process for producing finerenone (II) comprises steps 1), 2), and at least step 4). In one embodiment, the process for producing finerenone (II) comprises steps 1), 2), and at least step 5). In one embodiment, the process for producing finerenone (II) comprises steps 1), 2), and at least step 6). In one Embodiment, the process for producing finerenone (II) includes steps 1), 2), and at least step 7). In one embodiment, the process for producing finerenone (II) comprises steps 1), 2), and at least step 8). In one embodiment, the process for producing finerenone (II) comprises steps 1), 2), and at least step 9).

Examples of steps 3) to 9) are in EP3174875 B1 described. The revelation of EP3174875B1 is included in the present disclosure.

zur Herstellung von Finerenone nach Formel (II)

Another aspect of the invention is the use of the process according to the invention for producing 4-formyl-3-methoxybenzonitrile of the formula (I)

for the production of finerenone according to formula (II)

zur Herstellung von 4-Formyl-3-Methoxybenzonitril der Formel (I)

Another aspect of the invention is the use of 4-methyl-3-methoxybenzonitrile of formula (III)

for the production of 4-formyl-3-methoxybenzonitrile of the formula (I)

zur Herstellung von 4-Formyl-3-Methoxybenzonitril der Formel (I)

Another aspect of the invention is the use of 3-methoxy-4-(dibromomethyl)benzonitrile of the formula (IV)

for the production of 4-formyl-3-methoxybenzonitrile of the formula (I)

zur Herstellung von Finerenone nach Formel (II)

Another aspect of the invention is the use of 4-methyl-3-methoxybenzonitrile of formula (III)

for the production of finerenone according to formula (II)

zur Herstellung von Finerenone nach Formel (II)

Another aspect of the invention is the use of 3-methoxy-4-(dibromomethyl)benzonitrile of the formula (IV)

for the production of finerenone according to formula (II)

zur Herstellung von 4-Formyl-3-Methoxybenzonitril der Formel (I) oder Finerenone nach Formel (II)

Another aspect is the use of the compound according to formula (V), (Va) or (Vb)

for the production of 4-formyl-3-methoxybenzonitrile of the formula (I) or finerenone of the formula (II)

Another aspect is the adduct according to formula (V)

erhältlich durch Schritt (i) des Aufreinigungsschritts.Another aspect is the adduct according to formula (V)

obtainable by step (i) of the purification step.

Further embodiments of the method according to the invention are shown below:
In one embodiment, the bromination reagent in step 1) is selected from N-bromosuccinimide, 1,3-dibromo-5,5-hydantoin, bromine and mixtures thereof. In one embodiment, a solvent is used in step 1). In one embodiment, a solvent selected from chloroform, chlorobenzene, dichlorobenzene and mixtures thereof is used in step 1). In one embodiment, in step 1), the bromination is carried out at temperatures of 50 to 120 ° C. In one embodiment, a radical starter is used in step 1). In one embodiment, a radical initiator selected from dibenzoyl peroxide and azobisisobutyronitrile is used in step 1). In In one embodiment, an aqueous hydrolysis is carried out in step 2). In one embodiment, in step 2), a solvent selected from water, dimethylformamide, dimethylacetamide, N-methylpyrolidone (NMP), tetramethylurea, chlorobenzene, dichlorobenzene and mixtures thereof is used. In one embodiment, an acidic additive is added in step 2). In one embodiment, an acidic additive selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid and mixtures thereof is added to the reaction mixture in step 2). In one embodiment, a basic additive is added to the reaction mixture in step 2). In one embodiment, a basic additive selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium phosphate, potassium phosphate, pyridine, triethylamine, ammonia and mixture thereof is added to the reaction mixture in step 2). In one embodiment, in step 2), the hydrolysis takes place at temperatures of 80 to 100 ° C. In one embodiment, in step 2), the reaction time in step 2) is 2 to 6 hours. In one embodiment, after step 2), one or more of the following steps selected from the extraction step, the purification step and the crystallization step are also carried out.

In one embodiment, after step 2), an intermediate purification of 4-formyl-3-methoxybenzonitrile of the formula (I) is further carried out, comprising the steps

(iii) reaction of 4-formyl-3-methoxybenzonitrile of the formula (I) with a bisulfite compound, the adduct according to formula (V)

erhalten wird,

is received,

(iv) basic cleavage of the adduct according to formula (V), where -formyl-3-methoxybenzonitrile of the formula (I)

erhalten wird.

is received.

umfassend das Verfahren zur Herstellung von 4-Formyl-3-Methoxybenzonitril der Formel (I)

nach einer der Ausführungsformen wie weiter oben beschrieben.One embodiment relates to a process for producing finerenone according to formula (II)

comprising the process for producing 4-formyl-3-methoxybenzonitrile of the formula (I)

according to one of the embodiments as described above.

zur Herstellung von Finerenone nach Formel (II)

verwendet werden.In one embodiment, one or more of the previously stated embodiments can be used to produce 4-formyl-3-methoxybenzonitrile of the formula (I).

for the production of finerenone according to formula (II)

be used.

verwendet werden.In one embodiment, one or more of the previously stated embodiments can be used to prepare 4-formyl-3-methoxybenzonitrile of the formula (I) or finerenone of the formula (II).

be used.

The invention relates to a compound according to formula (V), (Va) or (Vb)

zur Herstellung von 4-Formyl-3-Methoxybenzonitril der Formel (I) oder Finerenone nach Formel (II)

The invention relates to the use of the compound according to formula (V), (Va) or (Vb)

for the production of 4-formyl-3-methoxybenzonitrile of the formula (I) or finerenone of the formula (II)

Examples

Abbreviations H Hours G grams min minutes °C degrees Celsius mL milliliters mmol millimoles mol Mol aq. watery d. Th. the theory

Example 1: 4-Formyl-3-methoxybenzonitrile of the formula (I)

A mixture of 100.00 g (679.44 mmol) 4-methyl-3-methoxybenzonitrile (III), 213.69 g (747.38 mmol) 1,3-dibromo-5,5-hydantoin. and 5.58 g (33.97 mmol) of azobisisobutyronitrile in 800 mL of chlorobenzene were heated at 90 ° C for 4 h. The mixture was cooled to 20°C, 200 mL of water was added and the mixture was stirred at 20°C for 1 h. The precipitated solid was then filtered off and the phases were separated. The chlorobenzene phase was distilled off to a final volume of 400 mL. 400 mL of water and 34.25 g (407.66 mmol) of sodium bicarbonate were added and the mixture was then stirred under reflux for 4 h (intensive stirring of the two-phase mixture). The solution was cooled, the chlorobenzene phase was separated off, once with 200 mL of saturated aqueous. Sodium carbonate solution washed and then largely concentrated (up to the limit of stirrability) (under vacuum). 800 mL of heptane were added and cooled to 0 ° C and inoculated with 4-formyl-3-methoxybenzonitrile (I) 4-formyl-3-methoxybenzonitrile (I), stirring at 0 ° C for 4 h. The precipitated crystals were filtered off and then dried at 45 ° C under vacuum (20 mbar / nitrogen entrainment gas).

Yield: 82.67 g (75.5% of theory over two stages), purity (HPLC 100% method) > 99.3%, MS (EIpos): m / z = 162 [M ⁺ H] ⁺ , ¹ H NMR (300 MHz, DMSO-d6): δ =3.97 (s, 3H), 7.53 (d, 1H), 7.80 (s, 1H), 7.81 (d, 1H), 10.36(s, 1H).

Example 2: 4-Formyl-3-methoxybenzonitrile of the formula (I)

A mixture of 100.00 g (679.44 mmol) 4-methyl-3-methoxybenzonitrile 4-methyl-3-methoxybenzonitrile (III), 266.05 g (1495.00 mmol) N-bromosuccinimide and 8.22 g ( 33.97 mmol) of dibenzoyl peroxide in 800 mL of chloroform were refluxed for 4 h. The mixture was cooled to 20°C, 200 mL of water was added and the mixture was stirred at 20°C for 1 h. The precipitated succinimide was then filtered off and the phases were separated. The chloroform phase was distilled off to a final volume of 400 mL. 400 mL of water were added and the mixture was then stirred under reflux for 4 h (intensive stirring of the two-phase mixture). The solution was cooled, the aqueous phase was separated off, and the pH was adjusted by adding 10% aqueous. Sodium hydroxide solution to pH 7.0 and then washed the organic phase once with a 5% sodium sulfite solution. The chloroform phase was separated off and largely concentrated (under vacuum) (up to the limit of stirrability). 400 mL of ethyl acetate were added and distilled to a volume of approx. 150 mL (under vacuum). The mixture was cooled to -15° C. and the supersaturated solution was inoculated with 0.5 g of 4-formyl-3-methoxybenzonitrile (I), 4-formyl-3-methoxybenzonitrile (I), and stirred at -15° C. for 4 h. The precipitated crystals were filtered off and then dried at 45 ° C under vacuum (20 mbar / nitrogen entrainment gas).

Yield: 81.80 g (74.7% of theory over two stages), purity (HPLC 100% method) > 99.2% Example 3: 4-Formyl-3-methoxybenzonitrile of the formula (I)

A mixture of 100.00 g (679.44 mmol) 4-methyl-3-methoxybenzonitrile 4-methyl-3-methoxybenzonitrile(III), 8.22 g (33.97 mmol) dibenzoyl peroxide and 213.69 g (747. 38 mmol) 1,3-dibromo-5,5-hydantoin in 1000 mL chlorobenzene were heated at 90 ° C for 4 h. The mixture was cooled to 20°C, 200 mL of a 10% aqueous sodium sulfite solution was added and the mixture was stirred at 20°C for 1 h. The precipitated solid was then filtered off and the phases were separated. The chlorobenzene phase was distilled off to the limit of stirrability. 500 mL of dimethylformamide were added and the solvent was distilled off in vacuo to a final volume of approximately 250 mL. 250 mL of water were added and the mixture was then stirred at 90°C for 1 h. The solution was cooled to 20 ° C, 500 mL of methyl isobutyl ketone (MIBK) was added and stirred 15 minutes at 20°C. The organic phase was separated off and washed with 500 mL of a saturated sodium bicarbonate solution. The mixture was then washed with 250 mL of water. The organic phase was concentrated in vacuo to the limit of stirrability and 600 mL heptane was added. The mixture was cooled to 0°C and inoculated with 0.5 g of 4-formyl-3-methoxybenzonitrile (I) and the mixture was stirred at 0°C for 4 h. The precipitated crystals were filtered off and then dried at 45 ° C under vacuum (20 mbar / nitrogen entrainment gas).

Yield: 83.33 g (76.1% of theory over two stages), purity (HPLC 100% method) > 99.1% Example 4: 4-Formyl-3-methoxybenzonitrile of the formula (I)

A mixture of 100.00 g (679.44 mmol) 4-methyl-3-methoxybenzonitrile (III), 266.05 g (1495.00 mmol) N-bromosuccinimide and 8.22 g (33.97 mmol) dibenzoyl peroxide in 800 mL of chloroform was refluxed for 4 h. The mixture was cooled to 20°C, 200 mL of water was added and the mixture was stirred at 20°C for 1 h. The precipitated succinimide was then filtered off and the phases were separated. The chloroform phase was distilled off to a final volume of 400 mL. 400 mL of water were added and the mixture was then stirred under reflux for 4 h (intensive stirring of the two-phase mixture). The solution was cooled, the aqueous phase was separated off, and the pH was adjusted by adding 10% aqueous. sodium hydroxide solution to pH 7.0 and then washed the organic phase once with a 5% sodium sulfite solution. The chloroform phase was separated off and largely concentrated (under vacuum) (up to the limit of stirrability). Add 400 mL of ethyl acetate and distill to a volume of approx. 100 mL (under vacuum). 600 mL of heptane were added, 100 mL of solvent were then distilled off under vacuum, inoculated with 0.5 g of 4-formyl-3-methoxybenzonitrile (I), and stirred at 0 ° C for 4 h. The precipitated crystals were filtered off and then dried at 45 ° C under vacuum (20 mbar / nitrogen entrainment gas).

Yield: 80.92 g (73.9% of theory over two stages), purity (HPLC 100% method) > 99.3% Example 5: 4-Formyl-3-methoxybenzonitrile of the formula (I)

A mixture of 100.00 g (679.44 mmol) 4-methyl-3-methoxybenzonitrile (III), 213.69 g (747.38 mmol) 1,3-dibromo-5,5-hydantoin. and 5.58 g (33.97 mmol) of azobisisobutyronitrile in 800 mL of chlorobenzene were heated at 90 ° C for 4 h. The mixture was cooled to 20°C, 200 mL of water was added and the mixture was stirred at 20°C for 1 h. The precipitated solid was then filtered off and the phases were separated. The chlorobenzene phase was distilled off to a final volume of 400 mL. 400 mL of water were added and the mixture was then stirred under reflux for 4 h (intensive stirring of the two-phase mixture). The solution was cooled, the chlorobenzene phase was separated off, then 200 mL of saturated aqueous was added. Sodium carbonate solution washed and largely concentrated (up to the limit of stirrability) (under vacuum). 400 mL of ethyl acetate and 800 mL of heptane were added and 500 mL of solvent were distilled off in vacuo, cooled to 0 ° C and inoculated with 0.5 g of 4-formyl-3-methoxybenzonitrile (I), stirred at 0 ° for 4 h C The precipitated crystals were filtered off and then dried at 45 ° C under vacuum (20 mbar / nitrogen drag gas).

Yield: 82.02 g (74.9% of theory over two stages), purity (HPLC 100% method) > 99.2% Example 6: 4-Formyl-3-methoxybenzonitrile of the formula (I)

A mixture of 100.00 g (679.44 mmol) 4-methyl-3-methoxybenzonitrile (III), 213.69 g (747.38 mmol) 1,3-dibromo-5,5-hydantoin. and 5.58 g (33.97 mmol) of azobisisobutyronitrile in 800 mL of chlorobenzene were heated at 90 ° C for 4 h. The mixture was cooled to 20°C, 200 mL of water was added and the mixture was stirred at 20°C for 1 h. The precipitated solid was then filtered off and the phases were separated. The chlorobenzene phase is distilled off to a final volume of 400 mL. 400 mL of water and 20 mL of concentrated were added. Hydrochloric acid was then stirred under reflux for 4 hours (intensive stirring of the two-phase mixture). The solution was cooled, the organic phase was separated off and washed with 300 mL of an aqueous 5% aqueous solution. Sodium carbonate solution. The chlorobenzene phase was separated off and largely concentrated (up to the limit of stirrability) (under vacuum). 800 mL of heptane were added and cooled to 0°C and inoculated with 0.5 g of 4-formyl-3-methoxybenzonitrile (1), stirring at 0°C for 4 hours. The precipitated crystals were filtered off and then dried at 45° C. under vacuum (20 mbar/nitrogen carrier gas).

Yield: 82.56 g (75.4% of theory over two stages), purity (HPLC 100% method) > 99.2% Example 7: 4-Formyl-3-methoxybenzonitrile of the formula (I)

A mixture of 100.00 g (679.44 mmol) 4-methyl-3-methoxybenzonitrile (III), 266.05 g (1495.00 mmol) N-bromosuccinimide and 8.22 g (33.97 mmol) dibenzoyl peroxide in 800 mL of chloroform was refluxed for 4 h. The mixture was cooled to 20°C, 200 mL of water was added and the mixture was stirred at 20°C for 1 h. The precipitated succinimide was then filtered off and the phases were separated. The chloroform phase was distilled off to a final volume of 400 mL. 400 mL of water were added and the mixture was then stirred under reflux for 4 h (intensive stirring of the two-phase mixture). The solution was cooled and the organic phase was separated off. The chloroform phase was largely concentrated (under vacuum) (up to the limit of stirrability). A bisulfite adduct was then prepared to purify the aldehyde (I) as follows: 83.25 g (800 mmol) of sodium hydrogen sulfite were added to 400 mL of water. The chloroform phase was slowly added dropwise with vigorous stirring and chloroform was distilled off under vacuum. The precipitated solid (bisulfite adduct) was filtered off and washed twice with 300 mL of water each time. The solid was suspended in 400 mL of water and 500 mL of ethyl acetate was added. While stirring, the pH was adjusted by adding 30% aqueous. Caustic soda to pH 9.5. The ethyl acetate phase was separated off and washed once with 100 mL of 1N hydrochloric acid. 200 mL of ethyl acetate were added and distilled to a volume of approx. 150 mL (under vacuum). The mixture was cooled to -15°C and the supersaturated solution was inoculated with 0.5 g of 4-formyl-3-methoxybenzonitrile (I) and stirred at -15°C for 4 h. The precipitated crystals were filtered off and then dried at 45° C. under vacuum (20 mbar/nitrogen carrier gas).

Yield: 78.07 g (71.3% of theory over two stages), purity (HPLC 100% method) > 99.3% Example 8: Crystallization procedure for purifying the aldehyde of the formula (I)

85.00 g of 4-formyl-3-methoxybenzonitrile (I), raw (purity according to HPLC approx. 97.5%) were dissolved in 215 mL of a mixture of MIBK (methyl isobutyl ketone) and n-heptane (1:2 ) dissolved by heating to reflux (~ 95°C). It was stirred for 1 h at reflux. After 1 h the material was completely dissolved; The solution was slowly cooled to room temperature (in ~4h to 23 °C), precipitation of the product started at 75 °C. Then the suspension was stirred for 1 h at room temperature (~23°C) and isolated by filtration. The product was washed with 40 mL of a mixture of MIBK/n-heptane 1:2 and then dried under vacuum at 45 °C (20 mbar) overnight.

Yield: 73.6 g (86.6% of theory), purity (HPLC 100% method) > 99.7% Example 9: Purification of 3-methoxy-4-(dibromomethyl)benzonitrile

A small sample of 3-methoxy-4-(dibromomethyl)benzonitrile (IV) was purified using chromatography on silica gel (mobile phase: heptane/ethyl acetate = 15:1) and analyzed spectroscopically:
1HNMR (300 MHz in DMSO) δ : 7.88 (d, J ) 8.0 Hz, 1H), 7.62 (d, J ) 1.4 Hz, 1H), 7.53 (dd, J ) 8.0 and 1.5 Hz, 1H), 7.35 (see , 1H), 3.97 (s, 3H)

Claims (15)

Process for producing 4-formyl-3-methoxybenzonitrile of the formula (I),

comprehensive the steps Step 1) Reacting 4-methyl-3-methoxybenzonitrile of the formula (III)

with a bromination reagent, where 3-methoxy-4-(dibromomethyl)benzonitrile of the formula (IV)

is received, Step 2) Hydrolysis of 3-methoxy-4-(dibromomethylbenzonitrile) of formula (IV)

to the compound of formula (I)

The method of claim 1, wherein the bromination reagent in step 1) is selected from N-bromosuccinimide, 1,3-dibromo-5,5-hydantoin, bromine and mixtures thereof. A method according to claim 1 or 2, wherein in step 1) a solvent selected from chloroform, chlorobenzene, dichlorobenzene and mixtures thereof is used. A process according to any one of claims 1 to 3, wherein the bromination in step 1) is carried out at temperatures of 50 to 120°C. Method according to one of claims 1 to 4, wherein in step 1) a radical initiator selected from dibenzoyl peroxide and azobisisobutyronitrile is used. Method according to one of claims 1 to 5, wherein in step 2) an aqueous hydrolysis is carried out. Method according to one of claims 1 to 6, wherein in step 2) a solvent selected from water, dimethylformamide, dimethylacetamide, N-methylpyrolidone (NMP), tetramethylurea, chlorobenzene, dichlorobenzene and mixtures thereof is used. Method according to one of claims 1 to 7, wherein the reaction mixture in step 2) is added an acidic additive selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid and mixtures thereof. Method according to one of claims 1 to 8, wherein the reaction mixture in step 2) a basic additive selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, pyridine, triethylamine, ammonia and mixtures thereof is added. Process according to one of claims 1 to 9, wherein the hydrolysis in step 2) takes place at temperatures of 80 to 100°C. Method according to one of claims 1 to 10, wherein the reaction time in step 2) is 2 to 6 hours. The method according to any one of claims 1 to 11, wherein the method according to step 2) further comprises an intermediate purification of 4-formyl-3-methoxybenzonitrile of the formula (I) comprising the steps (v) reaction of 4-formyl-3-methoxybenzonitrile of the formula (I) with a bisulfite compound, the adduct according to formula (V)

is received, (vi) basic cleavage of the adduct according to formula (V), where -formyl-3-methoxybenzonitrile of the formula (I)

is received. Process for the preparation of finerenone (II) according to formula (II)

comprising step 1) and step 2) for producing 4-formyl-3-methoxybenzonitrile of the formula (I) according to one of claims 1 to 12.

Use of the process according to one of claims 1 to 12 for the production of 4-formyl-3-methoxybenzonitrile of the formula (I)

for the production of finerenone according to formula (II)

Use of 4-methyl-3-methoxybenzonitrile of the formula (III) or 3-methoxy-4-(dibromomethyl)benzonitrile of the formula (IV)

for the production of 4-formyl-3-methoxybenzonitrile of the formula (I) or finerenone of the formula (Π)